Sepsis and Septic Shock.
A normal bacterial inflammation is a highly regulated process whereby the defense system clears up bacteria. In humans with a weakened defense, the bacterium gets, an opportunity to proliferate (virtually uninhibitedly) and to break through to the blood stream. The presence of bacteria in the blood stream is called sepsis. Sepsis leads to the production of proinflammatory mediators by white blood cells (morkocytes and macrophages) in the blood. This reaction is crucial for a fast and efficient elimination of bacteria. However, if the inflammatory reaction persists too long, for instance due to disease-related immune suppression, this may eventually lead to severe fever, spontaneous blood clotting and damage of tissues due to oxygen deficiency and due to bactericidal products. In serious cases, organs (specifically kidney, heart and liver) may stop functioning and the patient may get into so-called septic shock, from which he may subsequently die.
Incidence.
In the United States alone, more than 500,000 patients a year develop septic shock, with an estimated incidence increase of about 1.5% a year, and the costs amount to $16.7 billion a year (Angus, 2001). Septic shock results in death in 20-80% of cases (depending on the definition used). The increasing use of invasive surgical techniques, chemotherapy and the application of immunosuppression in patients with organ transplants or inflammatory diseases constitute causes of an increasing number of cases of sepsis. The longer life expectancy of elderly people and patients having metabolic, neoplastic and immunodeficiency defects owing to improved medical care, also leads to populations at increased risk of bacterial infection.
Lipopolysaccharide and Lipoteichoic Acid.
Sepsis and septic shock are caused chiefly by Gram-negative bacteria (for instance E. coli and K. pneumoniae) and (to a lesser extent) Gram-positive bacteria (S. aureus and S. epidermidis).
Lipopolysaccharide (LPS) is the most important constituent of the outer membrane of Gram-negative bacteria. LPS is the most reactive component of Gram-negative bacteria. LPS activates mononuclear cells (monocytes and macrophages), after which these cells produce proinflammatory mediators such as cytokines (TNFα, IL-1.beta. IL-6) and oxygen radicals. This response is necessary for a fast and effective dealing with the bacterial infection, and plays a crucial role in the clearing up of the bacteria (Heumann, 2002). However, in case of an inadequate response, allowing the bacteria to continue to proliferate uninhibitedly, these mediators are responsible for the metabolic changes that lead to pathologic conditions and eventually to death, as demonstrated in rabbits, monkeys and mice.
The equivalent of LPS in Gram-positive bacteria is lipoteichoic acid (LTA), which possesses a structure that exhibits strong homology to that of LPS.
Current Clinical and Experimental Therapies.
The complexity of sepsis and the immunological defense render the development of pharmacological interventions more difficult. The standard treatment often consists in the administration of fluid and blood pressure raisers (so-called vasopressors) to normalize the blood pressure and the oxygen supply of organs, and antibiotics to inhibit the proliferation of bacteria (Rackow, 1991; Cohen, 1991; Wheeler, 1999), but this treatment is not sufficient to prevent the high mortality.
Most applied experimental strategies for treating sepsis have been aimed at inhibiting the proinflammatory response, for instance through capturing LPS, blocking the cytokine action or overall immune suppression.
However, various clinical studies have shown that LPS-neutralizing antisera are not effective in septic shock (Cohen, 1999). Likewise, experimental therapies with antibodies to inter alia TNFα (Fisher, 1996; Clark, 1998) and the IL-1 receptor (Fisher, 1994; Opal, 1997) proved not to be effective.
By means of a meta-analysis, it has been demonstrated that overall immune suppression increases the mortality resulting from sepsis (Cronin, 1995). A recent study in humans demonstrates that a polymorphism in the LPS receptor Toll-like receptor 4 (TLR4), which leads to a reduced inflammatory response against LPS, is associated with an increased sensitivity to severe bacterial infection (Kiechl, 2002). Furthermore, it is known that mice, which are deficient for the proinflammatory cytokine macrophage migration inhibitory factor (MIF), are less well capable of clearing up bacteria such as. Leishmania major (Satoskar, 2001) and Salmonella typhimurium (Koebernick, 2002).
Many suggestions have been made for treating sepsis or septic shock, all of which have in common that an LPS-binding peptide is administered to sepsis patients. The administration of these LPS binding peptides is typically aimed at the suppression of the LPS-induced activation of the immune system. The peptides to be administered can, for instance, be derived from LBP (LPS Binding Protein; see WO 95/25117), apoA and apoE (WO 98/07751), apoA1 (WO 95/25786; WO 99/16458; WO 99/16459; WO 99/16408; WO 99/16409), CAP18 (Larrick, 1994), CAP37 (U.S. Pat. No. 6,107,460; U.S. Pat. No. 5,650,392; U.S. Pat. No. 5,627,262; U.S. Pat. No. 5,607,916), CD14 (WO 96/20956), prophenin (WO 95/34289; WO 95/26747), polyphemusin (WO 02/00687) and LALF protein (U.S. Pat. No. 5,747,455). To date, however, all of these suggestions have not yielded an effective approach for sepsis and septic shock either.
Sepsis has great consequences for the lipoprotein metabolism. Patients who get to the clinic exhibit strongly lowered cholesterol levels in the blood, which normalize after successful antibacterial therapy. Research in vitro and in experimental animals has demonstrated that lipoproteins can offer protection against sepsis, but the complexity of lipoproteins (including composition, endogenous character) makes their clinical application more difficult. Also, the mechanism by which lipoproteins play a protective role is still unknown. It has been reported that infusion of protein-free triglyceride-rich lipid emulsions does not afford protection (Van der Poll, 1995), which indicates that it is precisely the protein components of lipoproteins that can play a large protective role in sepsis.